The present invention relates to a biodegradable drug delivery system comprising a plurality of microspheres between 40 μm and 200 μm in diameter that are effectively retained in the anterior chamber of the eye for an extended period (such as for about 1-12 months) without producing hyperemia. The microspheres generally contain a drug effective for the treatment of an ocular condition and a biodegradable polymer matrix that provides for continuous and sustained (>7 day) release of the drug following administration to the anterior chamber of the eye. The drug may be encapsulated and/or dispersed within the biodegradable polymer matrix. Pharmaceutical compositions comprising these microspheres, methods for making these microspheres, and methods of administering the microspheres to the anterior chamber (or optionally the vitreous body) of the eye to treat an ocular condition such as glaucoma, elevated intraocular pressure, and inflammation, are also described.
While microspheres and extruded implants have been used in the past for the localized delivery of a drug into the anterior or posterior segment of the eye, conventional microspheres and extruded implants suffer from certain drawbacks. Conventional microspheres used in ocular methods commonly have particle sizes ranging from about 1-30 μm. However, we have discovered that microspheres of this size are poorly tolerated inside the eye due to significant inflammation, which may be due to phagocytosis of the microspheres inside the eye. As a result severe hyperemia may occur when microspheres of this size are injected into an ocular region of the eye such as the anterior chamber or subTenon's space. Additionally, microspheres that are less than about 30 or 40 μm in diameter are not effectively retained in the anterior chamber after intracameral administration. While not wishing to be bound by any theory, it is believed that microspheres with diameters less than about 30 μm are quickly cleared from the anterior chamber through the trabecular meshwork, a 3 dimensional sponge-like structure with pore sizes ranging from 20-30 μm.
Extruded implants have also been investigated for administration to the anterior chamber of the eye. However, the implants must be very small to fit through a small gauge needle (25 gauge or smaller). The implants must also be small enough to fit into the angle formed by the cornea and iris without touching the corneal endothelium. This limits the size of the implant and greatly reduces the potential drug load. These size limitations restrict the use of implants to only very potent compounds. Additionally, it is technically very challenging to manufacture, weigh, cut, and load these implants into an injectable device.
An additional disadvantage of a typical PLGA extruded implant used for this route of administration is swelling. An implant may swell to 2-3 times its original size after being injected into the anterior chamber. Swollen implants may damage corneal endothelium cells, severely limiting the population of patients suitable for this treatment.
Accordingly, the present disclosure describes a biodegradable “microsphere” drug delivery system that can be used for intracameral administration of a drug with little if any of the side effects described above. The system comprises a plurality of biodegradable, drug-containing, spherical (or substantially spherical) particles (microspheres) with diameters (and therefore particles sizes) ranging from 40 to 200 μm, with a mean diameter between 60 and 150 μm. In one embodiment the microspheres in the drug delivery system have diameters of between about 100 μm and about 180 μm with a mean diameter of between about 100 and about 150 μm.
The particle size requirement ensures that phagocytosis of the particles within the eye is minimized or eliminated altogether and prevents immediate clearance of the particles across the trabecular meshwork. Nevertheless, despite their size, the microspheres can be easily injected into the anterior chamber or other ocular region in the eye using small gauge needles (25 gauge and smaller). Furthermore, a much higher dose can be given since the diameter and length limitations of rod shaped implants are overcome. Doses up to a few milligrams of drug can be administrated via 20 μL injections. In comparison, most extruded implant system active dosages are less than 1 mg. The microspheres do not swell as much as typical implants as they hydrate, hence more total polymer can be administered. Microspheres also allow for easy dose adjustment, and can be readily manufactured in gram to kilogram quantities using aseptic processing techniques. Moreover, with a suitable polymer or polymer combination, the microspheres can provide for the sustained release of a therapeutic agent directly into the anterior chamber of the eye to more effectively treat an ocular condition of the anterior segment of the eye without the need for daily administration of the agent, which may or may not effectively reach the affected region of the eye in an effective manner.